Researchers Discover New Chromosome Evolution Pattern

Posted July 22, 2005

COLLEGE STATION, July 22, 2005 - Breakages in chromosomes in
mammalian evolution have occurred at preferred rather than random
sites as long thought, and many of the sites are involved in human
cancers, an international team of 25 scientists has discovered.

The researchers, reporting in the July 22 issue of the journal
Science, also found that chromosomal evolution has accelerated,
based on the rate of breakages and reorganization, since the
extinction of dinosaurs 65 million years ago.

In a study led by Harris A. Lewin of the University of Illinois
at Urbana-Champaign and William J. Murphy of Texas A&M
University, the organization of chromosomes of humans, mice, rats,
cows, pigs, dogs, cats and horses was compared at high
resolution.

"This study has revealed many hidden secrets on the nature and
timing of genome evolution in mammals, and it demonstrates how the
study of basic evolutionary processes can lead to new insights into
the origin of human diseases," said Lewin, director of the
Institute for Genomic Biology at Illinois and a professor of animal
sciences.

The multi-species comparison was aided by a computer
visualization tool - the "Evolution Highway"- developed by
collaborators at the Automated Learning Group at the National
Center for Supercomputing Applications at Illinois. Other lead
participants were from the University of California at San Diego
and the Genome Institute of Singapore.

The speed-up of evolution since dinosaurs disappeared surprised
the researchers, who studied a computer-generated reconstruction of
genomes of long extinct mammals, including the ancestor of the
majority of living placental mammals of 94 million years ago.

"Based on our findings of the mammalian rate speed-up, we
postulate that early mammals, with conservative body plans,
retained fairly conserved genomes, as evidenced in the striking
similarities in the reconstructed ancestral genomes," Murphy
said.

"The widespread origin and diversification of most mammalian
orders after the K-T extinction, due to exploitation of new
ecological niches, may have facilitated isolation and opportunities
for the fixation of karyotypic differences," said Murphy, a
professor of veterinary integrative biosciences.

The K-T extinction occurred 65 million years ago as the
Cretaceous Period closed and the Tertiary Period began. The
Cretaceous-Tertiary Boundary, a defining moment marked throughout
the world by a thin layer of iridium-rich clay between the rocks of
the two periods, is believed to have resulted from a massive comet
or asteroid strike.

The study's data, Murphy added, provide a potential link between
post-K-T isolation and the accelerated development of
species-specific chromosomes. Since the K-T extinction, rates of
chromosomal evolution among the species have increased from
two-to-five fold, the researchers reported.

Rates of changes were obtained by analyzing the placements of
breakpoints in the genomes of the species studied. A breakpoint is
where one chromosome has split and the DNA is rearranged by the
insertion of a piece from another chromosome or a different part of
the same chromosome.

Breakpoints have been implicated as potentially major triggers
for cancers and many other human diseases. "We looked closely at
these breakpoints, asking if there are specific DNA signatures in
these regions," Lewin said. "The answer is, we still don't know,
but in the human there is a high frequency of segmental duplication
around the sites of breakage. We are interested in characterizing
the genes and their functions in these regions."

The multi-species comparison showed significant overlapping with
breakpoints that occur in a variety of human cancers, Lewin said.
"While more work needs to be done to clarify this relationship, it
is clear that the overlap is real, and that there is likely to be
biological significance to this discovery."

The researchers theorize that chromosome rearrangements that
result in the activation of cancer-causing genes are related to the
propensity of chromosomes to break and form new combinations as new
mammalian species evolve.

In all, 1,159 pair-wise breakpoints were found among the genomes
of human and six non-primate species. Using a bioinformatics tool,
researchers aligned and compared the breakpoints across species and
constructed an evolutionary scenario for chromosomal rearrangements
among all genomes and ancestors. They found 492
evolutionary-specific breakpoints and analyzed them for segmental
duplication; 40 breakpoints were considered to be primate
specific.

"Understanding the features of the DNA sequence in and around
the evolutionary breakpoint regions is of key importance in
determining why chromosomes break in specific regions," said Denis
Larkin, a visiting animal scientist at Illinois and a principal
author.

The researchers found that chromosomes tend to break in the same
places as species evolve. Evidence for such a pattern had been
suggested previously by Larkin and Lewin and by study co-authors
Pavel A. Pevzner and Glenn Tesler, both of the University of
California at San Diego. However, the new study is the first to
show the phenomenon on a genome-wide basis by multi-species
comparison.

"Finding rearrangement hotspots in mammalian genomes is a
paradigm shift in the study of chromosome evolution," said Pevzner,
a professor of computer science at the University of California at
San Diego. The next important questions, he added, involve what it
is that makes some regions fragile and how fragility in an
evolutionary context is related to fragility in cancer.

The regions immediately flanking breakpoints, they discovered,
have more genes than the rest of the genome on average.

"One of the most gene dense regions of the human genome," the
authors wrote, "is characterized by recurrent breaks in different
mammalian lineages (dog, cat, cattle, rodents), marked by large
amounts of gene turnover and variation in centromere placement."
(Centromere refers to highly condensed and constricted regions of
chromosomes, where spindle fiber is attached during mitosis.)

Scientists at several other institutions contributed key
genome-mapping information to the project.

Mapping data for the dog genome was provided by scientists at
the U.S. National Human Genome Research Institute and French
National Center for Scientific Research (CNRS). Cat-mapping data
was contributed by the US National Cancer Institute.

Scientists at Illinois, Texas A&M University and the
National Institute for Agricultural Research in France provided
genome maps of cattle, horses and pigs. The genome maps of humans,
mice and rats were available from public sources.

"None of this would have been possible without the strategic
investments by the National Institutes of Health and by the U.S.
Department of Agriculture in the genome projects of humans, model
and agriculturally important organisms," Lewin said. "It's a
perfect example of the unity of biology when studied at the level
of DNA. Many more surprises await us as we relate genomes to
biology, and these surprises will lead to better understanding of
how species evolve and what peculiarities in their genomes cause
one species to have a high rate of cancer and others not."

Contact: William Murphy at (979) 848-0906 or email at
wmurphy@cvm.tamu.edu